To investigate the efcacy and safety of omega-3 fatty acids (O3FA) in treating depressive disorders in children and adolescents.
Trang 1RESEARCH ARTICLE
Omega-3 fatty acids for the treatment
of depressive disorders in children
and adolescents: a meta-analysis of randomized placebo-controlled trials
Li Zhang1, Huan Liu2, Li Kuang2, Huaqing Meng2 and Xinyu Zhou2*
Abstract
Background: To investigate the efficacy and safety of omega-3 fatty acids (O3FA) in treating depressive disorders in
children and adolescents
Method: We conducted a comprehensive search in electronic databases and hand-searched articles included for
rel-evant studies We included randomized controlled trials which studied on O3FA for treatment of children and adoles-cents with depression The standard mean differences (SMDs) and the odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by a random-effects model The primary outcomes were end-point depressive symptoms scores (efficacy) and all-cause discontinuation (safety) The secondary outcome of response rate was also assessed Subgroup analyses were performed by age, severity of depression and dosage Risk of bias assessment was performed based on the Jadad score and the Cochrane Collaboration’s risk-of-bias method
Results: A total of four studies with 153 participants were included In terms of efficacy, there was no significant
dif-ference of end-point depressive symptoms scores between O3FA and placebo (SMD = − 0.12, 95% CI − 0.53 to 0.30,
= 30%) In terms of safety, the all-cause discontinuation showed no statistical significance between O3FA
= 0%) The response rate of O3FA was also not significant better
= 71%) Besides, there were also no significant differ-ences in those subgroup analyses outcomes The risk of bias of included trials were not high
Conclusions: Only considering the limited evidence of O3FA in the acute treatment of major depressive disorder, it
did not seem to offer a clear advantage for children and adolescents
Keywords: Omega-3 fatty acids, Pediatric, Depression, Meta-analysis
© The Author(s) 2019 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creat iveco mmons org/licen ses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Background
Depression is a common and serious mental disorder
As reported, there are more than 350 million depressed
people all over the world [1] As to pediatric depression,
the prevalence is also high, with approximately 2.8% of
children and 5.6% of adolescents worldwide [2] A 70%
chance of pediatric depression will relapse in 5 years,
and half of young people would experience a recurrence
at least once during their adult life [3] Pediatric depres-sion is always under-diagnosed, because they may have only atypical depressive manifestations, such as irritabil-ity, mood fluctuating, and school refusal [4 5] Depres-sion does great harm to young people’s social ability, and
it is a major risk factor for suicide in children and ado-lescents [1 6] There are mainly two therapies: psycho-therapy and pharmacopsycho-therapy Although psychopsycho-therapy
is recommended as the first-line treatment for depres-sion in children and adolescent [6], the effect is always mild [4] Antidepressants are widely used in clinic and
Open Access
*Correspondence: xinyu973@126.com
Medical University, Yixueyuan Road, Yuzhong District, Chongqing 400016,
People’s Republic of China
Full list of author information is available at the end of the article
Trang 2for moderate to severe pediatric depression,
antidepres-sants and psychotherapy may be started concurrently [6]
However, in 2016, a network meta-analysis including 34
randomized placebo-controlled trials (RCTS) concluded
that most antidepressant drugs did not seem to offer
a clear benefit to pediatric depression [7] And as early
as in 2004 the US Food and Drug Administration (FDA)
alerted clinicians to the increased risk of suicidality
(sui-cidal thinking and behavior) in children and adolescents
associated with antidepressants use [8]
Omega-3 fatty acids (O3FA), a kind of nutrients, is
composed of eicosapentaenoic acid (EPA) and
doco-sahexaenoic acid (DHA), which cannot be synthesized
efficiently by human body, so dietary intake is the main
source, such as fish oil, seafood, flaxseed oil and perilla
oil [9] Recently, researches found that O3FA
supplemen-tation might be effective for several neuropsychiatric
dis-orders, such as attention deficit hyperactivity disorder
(ADHD) and autism spectrum disorder (ASD) [10–12]
It was also reported that higher fish consumption was
related to a reduced depression risk [13, 14] and O3FA
was an effective adjunctive treatment for adult depression
[15, 16] Several meta-analyses and reviews also showed
that supplementation of O3FAs could relieve symptoms
of depression for adult age groups [17–19], but no such
evidence especially studied in depressed children and
adolescents Therefore, we conducted this meta-analysis
to pool present evidences on efficacy and safety of O3FA
compared to placebo in the treatment of children and
adolescents with depressive disorders
Method
Literature search
We conducted a comprehensive search in the
follow-ing electronic databases, includfollow-ing PubMed, Embase,
Cochrane Library, Web of Science, and PsycINFO
cita-tions, as well as some international trials registers,
including WHO’s trials portal, US ClinicalTrials.gov,
EU Clinical Trials Register and Australian New Zealand
Clinical Trials Registry, up to July 2019 The following
search terms were used: (‘omega-3’ or ‘n − 3’ or
‘polyun-saturated fatty acid*’ or ‘un‘polyun-saturated fatty acid*’ or ‘PUFA’
or ‘eicosapentaenoic acid’ or ‘docosahexaenoic acid’ or
‘EPA’ or ‘DHA’) and (‘child*’ or ‘adolesc*’ or ‘pediatri*’)
and (‘depress*’ or ‘dysthymi*’ or ‘affective disorder*’ or
‘mood disorder*’) Relevant articles were also
hand-searched for eligible reports No limitations were applied
in the search
Selection criteria
We included: (1) RCTs with both parallel arms and
cross-over design (for cross-cross-over trials, we only used data from
the pre-crossover phase); (2) children (aged 6–12) and/or
adolescents (aged 13–18) with depressive disorders; (3) the intervention group could be O3FA treatment, or any component of it (EPA or DHA) No combined treatments like antidepressants or psychotherapy; (4) the comparison group should be placebo treatment; (5) efficacy outcome was assessed by depression scales The most common questionnaire or instrument used in the youth are The Children’s Depression Rating Scale (CDRS), revised CDRS (CDRS-R), Beck Depression Inventory (BDI) and Children’s Depression Inventory (CDI) We used the end-point score of depressive scale in each group as our primary efficacy outcome The secondary efficacy out-come was the response rate to omega-3 treatment The response rate was defined as ≥ 50% change from baseline
on depression score or a score of ≤ 28 at the end-point of
a trial on the CDRS-R [20] We also investigated all-cause discontinuation as safety outcome We excluded: (1) tri-als without random design or with just quasi-random design; (2) data of outcomes couldn’t be acquired; (3) studies with duplicated data Two authors (ZL and ZXY) reviewed all the screened trials independently according
to the above inclusion and exclusion criteria with strong
interrater agreement (κ = 0.90).
Data collection and risk of bias assessment
The following data were collected: publication informa-tion (the first author, publicainforma-tion year, study country), study and patients characteristics (study design type, sample size, age group, diagnostic criteria, severity of depression, rating scales, daily dosage and duration
of O3FA, ratio or dosage of EPA and DHA), outcome data (baseline data, post-treatment data, drop-out rate, adverse events)
Risk of bias of the selected studies was assessed by the modified Jadad score [21] and the Cochrane Collabora-tion’s risk-of-bias method [22] simultaneously Accord-ing to the modified Jadad score, we appraised risk of bias from four domains, including generation of allocation sequence, allocation concealment, investigator blind-ness, and description of withdrawals and dropouts The specific scoring method was shown in Additional file 1 Figure S1
All of the above data extraction and risk of bias assess-ment were finished by the two reviewers (ZL and ZXY) independently When meeting missing data or informa-tion, one author would e-mail the authors for further acquisition Disagreements were resolved by discussion
Statistical analysis
RevMan 5.3 version software and Stata 13.0 were used
to perform all the analyses in the meta-analysis We adopted standard mean differences (SMDs) with 95% confidence intervals (CIs) to estimate effect size of
Trang 3continuous variables and the odds ratios (ORs) with
95% CIs to estimate effect size of dichotomous
vari-ables For continuous variables, difference of the
end-point data with standard deviation (SD) between
O3FA and placebo was the effect value [23] A
ran-dom-effects model was chosen to calculate the effect
sizes for expected heterogeneity If SD was
unavail-able in a article and could not contact the authors, we
would be calculate it from reported P values, t values,
CIs or standard errors (SEs) in the article [24] The
heterogeneity was calculated by the test of
inconsist-ency (I2) [25] To investigate the possible sources of
heterogeneity, we conducted subgroup analyses The
publication bias was evaluated by Egger tests when
there were more than ten trials [26] A two-sided
P value of less than 0.05 was considered statistically
significant
Results
Selection of studies
With the keywords above, a total of 993 records was yielded preliminarily, of which 990 records were from electronic databases and three records were from hand-search After removing the 325 duplicates, 668 records were reviewed based on titles and abstracts And then, 14 potentially eligible records were screened out for full-text review With careful review and strict criteria, we finally included four RCT trials in this meta-analysis [27–30] The flow diagram was shown in Fig. 1 The 14 excluded records were shown in Additional file 2: Table S1
Description of the included studies
Most of the included studies were published in recent
2 years except the one by Nemet [29] Of the four included studies, two were from America [27, 28],
3 non-randomised design
4 included bipolar disorders
1 duplicated data
2 unavailable data
4 records included in meta-analysis
668 records for tles and abstracts
review
14 records for full-text review
654 records excluded
530 trials not depressive disorder or omega-3
118 trials not original inves ga ons
15 trials not RCTs
11 trials in adults
975 records iden fied through
electronic databases:
PubMed n=307 Embase n=54 Cochrance Library n=257
Web of Science n=292 PsycINFO cita ons n=65
3 addi onal records iden fied through bibliographies
15 records iden fied through interna onal trials registers:
WHO’s trials portal n=5
US ClinicalTrials.gov n=10
EU Chilnical Trials Register n=0
Australian New Zealand Clinical Trials Registry n=0
325 duplicates excluded
Fig 1 Flow diagram indicating the process of selecting eligible studies
Trang 4whereas one from Europe [30] and the remaining one
from Asia [29] Two studies were conducted in children
[27, 29], while the other two were performed in
adoles-cents [28, 30] However, mean sample size was 38
partici-pants, in which only one study by Gabbay [28] recruited
more than 50 participants Most participant
experi-enced moderate to severe depressive symptoms at
base-line on the depression rating scales In the intervention
groups, all the participants received O3FA with a fixed
ratio of EPA to DHA and all the ratios of EPA to DHA
were higher than 1:1, but there was still a significant
dif-ference in the daily intake between studies (400 mg/day
to 2289 mg/day) None of the studies provided a single
ingredient oil The whole treatment duration was
rela-tively long with a mean duration of 12.5 weeks Three
studies chosen CSDR or CSDR-R [27–29] and one study
applied CDI [30] to assess improvement in depressive
symptoms The characteristics of the included studies
were shown in Table 1
Risk of bias in the included studies
Generally, the quality of the included studies were not
high In the study by Nemets [29], the capsule used in
the O3FA group was different from the one used in the
placebo group in tone of internal color This could result
in failure in blinding of intervention We found the
num-ber of response in the placebo group was 0 in that study,
which might be biased caused by failure in blinding of
intervention The result of the modified Jadad scores
was shown in Table 1 The study quality assessed by the
Cochrane Collaboration’s risk-of-bias method was shown
in Additional file 3: Figure S2
Results for outcomes
A total of four studies with 153 participants evaluated
the efficacy and safety of O3FA for depressive disorders
in children and adolescents [27–30] In terms of efficacy
outcomes, the summary effect size of end-point
depres-sion scale scores, indicated that O3FA was not better
than placebo in treating children and adolescents with
depressive disorders, with a SMD of − 0.12 (95% CI
− 0.53 to 0.30, P = 0.58; I2= 30%, P = 0.23; Fig. 2a) The
other efficacy outcome we were concerned about, the
response rate, was also reported in three studies [27–29]
The response rate of O3FA group was still not superior
compared to that of placebo group with a OR of 1.57
(95% CI 0.26 to 9.39, P = 0.62; I2= 71%, P = 0.03; Fig. 2b)
In terms of safety outcome, the OR for the all-cause
discontinuation was 1.3 (95% CI 0.58 to 2.93, P = 0.53;
I2= 0%, P = 0.65; Fig. 2c), which meant no statistical
sig-nificance between the O3FA group and placebo group
Subgroup analyses were also performed in the
pri-mary efficacy outcome, stratified by mean age group
(≤ 12 years and > 12 years), severity of depression (mild and moderate to severe), and daily dosage of EPA (≤ 1 g/ day and > 1 g/day) No significance were found in those subgroups Results of subgroup analyses were presented
in Table 2 However, as to small number of included stud-ies, we couldn’t conducted sensitivity analysis or evalu-ated the publication bias
Discussion
To our best knowledge, this was the first meta-analysis focused on the efficacy and safety of O3FA in children and adolescents with depressive disorders Through a comprehensive search, we finally enrolled four eligible RCTs with 153 participants According to the results, O3FA had no positive effects in treating depression in children and adolescents with no statistical significance These results were in contrast to several previous meta-analyses specifically in adults [18, 19, 31, 32] But these meta-analyses in adults presented great heterogeneity between studies ranging from 64 to 84.1%, which was mainly from different populations, diagnostic criteria and interventions Of the four included studies in this meta-analysis, only one study by Nemets [29] had reported a beneficial efficacy of O3FA in the treatment of depression
in children and adolescents In that study, the response rate in the placebo group was 0, which was rare in clini-cal trials in depression among children and adolescents and might have magnified the efficacy of O3FA for chil-dren and adolescents Data from that trial could hardly
be generalized What’s more, diagnostic criteria, severity
of depression, daily dosage of EPA and DHA were all het-erogenous and trials were small scaled, so these results should be interpreted with cautions Eicosapentaenoic acid (EPA) was reported to be responsible for the benefi-cial effects of O3FA in treating depression in adult [33] and was recommended a higher ratio than 1:1 when used combined EPA + DHA [34, 35] In this review, we did not find greater benefits in studies with higher dose supple-mentation of EPA in young people
O3FA is associated with brain development and func-tion [36], which involve in maintaining membrane fluid-ity, influencing neurotransmission, decreasing levels of inflammatory mediators and affecting cognition function [17, 37, 38] The study by Grayson et al had shown that DHA is crucial for visual pathway connectivity and large-scale brain organization [39] Thus, O3FA was widely investigated in neuropsychiatric disorders Children and adolescents with ADHD had a deficiency in O3FA levels [40] and supplementation of O3FA could relieve clini-cal symptoms of ADHD in these young people [10, 12] Kean et al [41] conducted a randomised, double-blind, placebo-controlled study which investigated the effects
of marine oil extract on symptoms of ADHA in children
Trang 5A gr oup (mean)
daily dosage (g/d)
dosage (g/d)
Jadad sco
istad 2016 [27
2018 [28
Nemet 2006 [29
0.4 or 0.38
2017 [30
and depr
Trang 6The results indicated that marine oil extract may be
a preferable alternative treatments for children with
ADHD who have just mild or subclinical hyperactivity,
inattention and impulsivity Recent two meta-analyses also presented modest effects of O3FA in the reducing symptoms of ADHD children [42, 43] Amminger et al [11] found that O3FA could reduce hyperactivity and stereotypy symptoms in children with ASD However,
a review by James et al [44] had not find any improve-ments of symptoms after supplementation of O3FA in people with ASD The study by Woo et al [45] also found that supplements of O3FA were acceptable in the pediat-ric eating disorders population
Psychotherapy, mainly referring to cognitive behav-ioural therapy (CBT) and interpersonal psychotherapy (IPT), is still recommended as the first-line treatment for children and adolescents depression, unless the symptoms are severe [46–48] But for the management
of an uncomplicated or brief depression, mild psycho-social impairment, to begin treatment with education, support, and case management appears to be equally efficacious to psychotherapy [48, 49] With regards to antidepressants, fluoxetine is the first-line medication for depression in children and adolescents [7 47, 49] However, use of antidepressants is not recommended
in mild depressed youth considering serious adverse
Fig 2 Forest plots for the outcomes compared O3FA with placebo a Scores of depression rating scales; b the response rate; c all-cause
discontinuation
Table 2 Subgroup analyses of O3FA for the treatment
of depressive disorders in children and adolescents
EPA eicosapentaenoic acid
a Children were aged between 6 and 12 years and adolescents were aged
between 13 and 18 years
difference
Mean age (years) a
≤ 12 [ 27 , 29 ] − 0.45 (− 1.43, 0.53) 0.37 0 0.34
> 12 [ 28 , 30 ] 0.07 (− 0.36, 0.51) 0.74
Severity of depression
Mild [ 27 ] − 0.00 (− 0.96, 0.67) 1.00 0 0.67
Moderate to
severe [ 28 – 30 ] − 0.19 (− 0.79, 0.40) 0.52
Daily dosage of EPA (g/day)
≤ 1 [ 29 , 30 ] − 0.44 (− 1.44, 0.56) 0.39 0 0.36
> 1 [ 27 , 28 ] 0.07 (− 0.37, 0.50) 0.76
Trang 7effects of drugs, and antidepressants are thought
appro-priate only after an unsuccessful 3-month specific
psy-chological therapy in moderate to severe depressed
adolescents [47, 50] For a child with moderate to
severe depression and unresponsive to a 3-month
spe-cific psychological therapy, antidepressants should still
be prescribed with cautions [47]
O3FA has an excellent safety profile as dietary
nutri-ent Only one of the 153 participants stated more
fre-quent defecation after taking O3FA [30] No other
adverse events, even any mild discomforts, were
reported in the included studies in this review More
than that, no published literature had reported any side
effects of O3FA so far As no participant was
discontin-ued for adverse events, the outcome of discontinuation
for adverse events was not assessed Meanwhile, the OR
for all-cause discontinuation indicated no difference
between O3FA and placebo
This review has several limitations Firstly, number of
studies on children and adolescents with depressive
dis-orders was small Only four studies met our inclusion
criteria And in the only four eligible studies, the sample
sizes were really small with the biggest enrollment of 51
participants This downgraded the strength of evidence
directly Secondly, diagnostic criteria, severity of
depres-sion, daily dosage of EPA and DHA were heterogenous
in those included studies However, due to small
num-ber of the included studies, the value of I2 may have
lim-ited statistical power in finding heterogeneity Thirdly, as
polyunsaturated fatty acids are common nutrients in our
diets, and baseline dietary intake varies in different
pop-ulation [51] However, none of the included studies had
taken this into consideration in the study design
Conclusions
The evidence available indicated no efficacy of O3FA
for the treatment of children and adolescents
How-ever, for small number of trials and sample sizes, the
strength of evidence was weak Nevertheless, O3FA
were safe without adverse events occurring
Supplementary information
org/10.1186/s1303 4-019-0296-x
Additional file 1: Figure S1 The modified Jadad score
Additional file 2: Table S1 Reasons for excluding the 10 studies
Additional file 3: Figure S2 Risk of bias assessed by the Cochrane
Col-laboration’s risk-of-bias method.
Abbreviations
BDI: Beck Depression Inventory; CDI: Children’s Depression Inventory;
CDRS: Children’s Depression Rating Scale; CI: confidence interval; DHA:
docosahexaenoic acid; EPA: eicosapentaenoic acid; FDA: Food and Drug Administration; O3FA: omega-3 fatty acids; OR: odds ratio; RCT : randomized placebo-controlled trial; SE: standard error; SMD: standard mean difference.
Acknowledgements
Not applicable.
Authors’ contributions
LZ and XYZ contributed towards the study design LZ, HL and XYZ contributed towards he identification of eligible studies and data extraction LZ, HL and XYZ contributed towards data analysis LZ, LK, HQM and XYZ contributed towards writing the manuscript All authors read and approved the final manuscript.
Funding
This work was supported by the National Natural Science Foundation of China (Grant No 81873800 and Grant No 81701342).
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
of Chongqing Medical University, Yixueyuan Road, Yuzhong District, Chong-qing 400016, People’s Republic of China
Received: 18 May 2019 Accepted: 3 September 2019
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50 Hazell P Depression in children and adolescents BMJ Clin Evid
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51 Osher Y, Belmaker RH, Nemets B Clinical trials of PUFAs in depression:
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